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Ref Type Journal Article
PMID (35817971)
Authors Ma X, Riaz N, Samstein RM, Lee M, Makarov V, Valero C, Chowell D, Kuo F, Hoen D, Fitzgerald CWR, Jiang H, Alektiar J, Alban TJ, Juric I, Parthasarathy PB, Zhao Y, Sabio EY, Verma R, Srivastava RM, Vuong L, Yang W, Zhang X, Wang J, Chu LK, Wang SL, Kelly DW, Pei X, Chen J, Yaeger R, Zamarin D, Zehir A, Gönen M, Morris LGT, Chan TA
Title Functional landscapes of POLE and POLD1 mutations in checkpoint blockade-dependent antitumor immunity.
Journal Vol Issue Date Pages Journal Short Title
Nature genetics 54 7 2022 Jul 996-1012 Nat Genet
URL
Abstract Text Defects in pathways governing genomic fidelity have been linked to improved response to immune checkpoint blockade therapy (ICB). Pathogenic POLE/POLD1 mutations can cause hypermutation, yet how diverse mutations in POLE/POLD1 influence antitumor immunity following ICB is unclear. Here, we comprehensively determined the effect of POLE/POLD1 mutations in ICB and elucidated the mechanistic impact of these mutations on tumor immunity. Murine syngeneic tumors harboring Pole/Pold1 functional mutations displayed enhanced antitumor immunity and were sensitive to ICB. Patients with POLE/POLD1 mutated tumors harboring telltale mutational signatures respond better to ICB than patients harboring wild-type or signature-negative tumors. A mutant POLE/D1 function-associated signature-based model outperformed several traditional approaches for identifying POLE/POLD1 mutated patients that benefit from ICB. Strikingly, the spectrum of mutational signatures correlates with the biochemical features of neoantigens. Alterations that cause POLE/POLD1 function-associated signatures generate T cell receptor (TCR)-contact residues with increased hydrophobicity, potentially facilitating T cell recognition. Altogether, the functional landscapes of POLE/POLD1 mutations shape immunotherapy efficacy.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
POLE A629D missense unknown POLE A629D lies within the polymerase domain of the Pole protein (PMID: 29352080). A629D has been identified in the scientific literature (PMID: 35817971, PMID: 31253177), but has not been biochemically characterized and therefore, its effect on Pole protein function is unknown (PubMed, Mar 2024).
POLE C333S missense unknown POLE C333S lies within the exonuclease domain of the Pole protein (PMID: 29352080). C333S has been identified in the scientific literature (PMID: 35817971), but has not been biochemically characterized and therefore, its effect on Pole protein function is unknown (PubMed, Mar 2024).
POLE E265K missense unknown POLE E265K does not lie within any known functional domains of the Pole protein (UniProt.org). E265K has been identified in the scientific literature (PMID: 35817971), but has not been biochemically characterized and therefore, its effect on Pole protein function is unknown (PubMed, Mar 2024).
POLE E277Q missense unknown POLE E277Q lies within the exonuclease domain of the Pole protein (PMID: 29352080). E277Q has been identified in the scientific literature (PMID: 35817971), but has not been biochemically characterized and therefore, its effect on Pole protein function is unknown (PubMed, Mar 2024).
POLE F876V missense unknown POLE F876V lies within the polymerase domain of the Pole protein (PMID: 29352080). F876V has been identified in the scientific literature (PMID: 35817971), but has not been biochemically characterized and therefore, its effect on Pole protein function is unknown (PubMed, Mar 2024).
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
POLE P286R melanoma sensitive unspecified CTLA4 antibody Preclinical Actionable In a preclinical study, a murine anti-CTLA4 antibody inhibited tumor growth and improved survival in a syngeneic mouse model of melanoma expressing POLE P286R (PMID: 35817971). 35817971
POLD1 E374K melanoma sensitive unspecified PD-1 antibody Preclinical Actionable In a preclinical study, a murine anti-PD1 antibody inhibited tumor growth in a syngeneic mouse model of melanoma expressing POLD1 E374K (corresponds to E372K in mouse) (PMID: 35817971). 35817971
POLE P286R melanoma sensitive unspecified CTLA4 antibody + unspecified PD-1 antibody Preclinical Actionable In a preclinical study, the combination of a murine anti-CTLA4 antibody and a murine anti-PD1 antibody inhibited tumor growth and improved survival in a syngeneic mouse model of melanoma expressing POLE P286R (PMID: 35817971). 35817971
POLE P286R colorectal cancer sensitive unspecified CTLA4 antibody Preclinical Actionable In a preclinical study, a murine anti-CTLA4 antibody inhibited tumor growth in a syngeneic mouse model of colorectal cancer expressing POLE P286R (PMID: 35817971). 35817971
POLE P286R melanoma sensitive unspecified PD-1 antibody Preclinical Actionable In a preclinical study, a murine anti-PD1 antibody inhibited tumor growth and improved survival in a syngeneic mouse model of melanoma expressing POLE P286R (PMID: 35817971). 35817971
POLE V411L melanoma sensitive unspecified PD-1 antibody Preclinical Actionable In a preclinical study, a murine anti-PD1 antibody inhibited tumor growth in a syngeneic mouse model of melanoma expressing POLE V411L (PMID: 35817971). 35817971
POLE P286R colorectal cancer sensitive unspecified PD-1 antibody Preclinical Actionable In a preclinical study, a murine anti-PD1 antibody inhibited tumor growth in a syngeneic mouse model of colorectal cancer expressing POLE P286R (PMID: 35817971). 35817971
POLD1 L474P melanoma sensitive unspecified PD-1 antibody Preclinical Actionable In a preclinical study, a murine anti-PD1 antibody inhibited tumor growth in a syngeneic mouse model of melanoma expressing POLD1 L474P (corresponds to L472P in mouse) (PMID: 35817971). 35817971
POLE P286R colorectal cancer sensitive unspecified CTLA4 antibody + unspecified PD-1 antibody Preclinical Actionable In a preclinical study, the combination of a murine anti-CTLA4 antibody and a murine anti-PD1 antibody inhibited tumor growth in a syngeneic mouse model of colorectal cancer expressing POLE P286R (PMID: 35817971). 35817971